The present invention relates to compositions and methods for decreasing IgE production and IgE levels in mammalian subjects and treating secondary allergic responses.
Allergic reactions include four types, i.e., types I, II, III and IV. The type I (immediate-type, anaphylactic) allergic reaction is triggered by the reaction-relating-factor immunoglobulin E (hereinafter abbreviated as an IgE antibody). The reaction steps can be divided roughly into the following three steps. The first step is a sensitization step involving IgE antibody production and binding of the resulting IgE antibodies to mast cells or basophils. The second step involves degranulation of the mast cells or basophils and release of chemical mediators. The third steps involves onset of effects of the released chemical mediators on the target organs. Thus, the type I allergic reaction against foreign antigens leads to onset of symptoms through the above reaction steps.
Only symptomatic treatments by inhibiting the above second and/or third reaction steps have been carried out to treat allergic diseases. That is, the treatments are carried out by inhibiting the release of chemical mediators accompanying the degranulation and/or by inhibiting allergic reactions induced by the released chemical mediators. These symptomatic treatments have been known to be effective not only in systemic administration of anti-allergic agents but also in their topical administration to the nose, etc. However, the effects of the treatments are limited because the treatments do not inhibit IgF antibody production which is the basic first step of the type I allergic reaction.
As fundamental remedies against the type I allergic reaction, agents inhibiting or modulating the above first step, namely IgE antibody production inhibitors, are being developed.
Type I allergy is an inflammatory response which is elicited as the invasion of foreign agents into the body which results in the release of various enzymes and chemical mediators, such as histamine and leukotrienes, from mast cells and eosinophils, which in turn induce tissue-damaging inflammations. The allergic response, when generalized, can lead to a systemic and often life threatening reaction known as anaphylactic shock.
In pollen allergy for example, symptoms occur preferentially in the nose and eye. In recent years, there has been a rapid increase in the number of patients who complain of the so-called pollinosis symptoms due to pollens of cedar and other allergenic plants, resulting in, for example, allergic conjunctivitis and allergic rhinitis (eye watering, sinus congestion, nasal congestion, sneezing and the like). For the prevention of pollen disease, a prophylactic treatment with antiallergic agents, a symptomatic treatment with antihistamines and steroids, and hyposensitization therapy are generally indicated.
However, there is not available as yet an antiallergic agent effective enough and devoid of nocive side effects as a preventive drug, while the antihistamines and steroids in current use for symptomatic treatment have the problem of side effects.
Conditions in which IgE is elevated:
Atopy provides the hereditary basis for allergic responses. The condition is a congenital hypersensitivity to specific agents, and is usually manifested as bronchial asthma and allergic rhinitis. Atopic dermatitis is an inflammatory disease of the skin which may arise because of a predisposition and which is often characterized by areas of localized itch. It is also known that as the affected area is scratched, the local eruption is aggravated so that the disease runs a chronic course. Moreover, the pruritus associated with atopic dermatitis develops suddenly in many cases and tends to be provoked and intensified by the slightest stimulation.
A variety of treatments have been attempted for atopic dermatitis, but they have proved unsuccessful. The current therapeutic modality for this disease consists of the topical treatment primarily with adrenocorticoids and, as an adjunct therapy, antipruritic agents such as antihistamines. But since these drugs are not without side effects, the advent of a safe and more sure-acting drug for the prevention and treatment of atopic dermatitis has been anticipated.
Patients with bronchial asthma are rapidly increasing in number and present a serious problem everywhere in the world today. Bronchial asthma is an airway disease, the cardinal manifestation of which is respiratory distress due to paroxysmal airway constriction, which is life threatening at times. While many etiologic agents are usually involved in the onset of bronchial asthma, the chief cause is generally believed to be an increased airway responsiveness due to allergic factors associated with inhaled antigens such as cockroaches, ticks, pollens, dust and so on.
For the treatment of bronchial asthma, prophylaxis with antiallergic drugs and symptomatic treatment with beta.-receptor stimulants and steroids are practiced today, but there is no antiallergic drug effective enough as a prophylactic. Further, the problem of side effects has been pointed out frequently with the use of beta.-receptor stimulants and steroids used for symptomatic treatment.
As mentioned earlier, the first step in the pathogenesis of an allergic response is the production of immunoglobulin E (IgE) antibody in response to an allergen. Upon exposure to allergens, the B cells of responsive individuals secrete IgE molecules specific to the allergen. IgE molecules bind to the high affinity IgE receptor present on mast cells and basophils. IgE binding activates the release of a variety of vasoactive mediators that promote allergic and inflammatory responses. Activation occurs whenever two or more high affinity IgE receptors are cross linked via bound IgE molecules that in turn form an aggregate with an allergen molecule.
Such aggregation initiates a biochemical cascade that releases histamine and proteases from cytoplasmic granules and leads to the synthesis of prostaglandins, leukotrienes, cytokines and other effectors of the hypersensitivity response. Mast cells and basophils accumulate at sites of inflammation and, upon activation, secrete hemopoietic growth factors such as granulocyte/macrophage colony-stimulating factor, interleukin-3, and interleukin-6. These factors propagate the inflammatory response by recruiting, priming, and activating inflammatory cells such as neutrophils, macrophages and eosinophils. The activated cells accumulate in areas of ongoing inflammation, tumor invasion, angiogenesis, fibrosis, and thrombosis. The IgE-dependent activation of cells via high affinity IgE receptors results in an inflammatory response directed towards local tissue defense, tissue maintenance and remodeling, and immunoregulation (Gagari, E. et al (1997) Blood 89:2654-2663). Preventing the IgE activation of cells would be an important step in preventing or treating conditions in which elevated IgE levels are a hallmark.
Currently, therapy for treatment of inflammation predominantly involves the use of glucocorticosteroids. Other anti-inflammatory agents are used including cromolyn and nedocromil. Symptomatic treatment with beta-agonists, anticholinergic agents and methyl xanthines are clinically beneficial for the relief of discomfort but fail to stop the underlying inflammatory processes that cause the disease. The frequently used systemic glucocorticosteroids have numerous side effects, including, but not limited to, weight gain, diabetes, hypertension, osteoporosis, cataracts, atherosclerosis, increased susceptibility to infection, increased lipids and cholesterol, and easy bruising. Aerosolized glucocorticosteroids have fewer side effects but can be less potent and have side effects, such as thrush.
Other anti-inflammatory agents, such as cromolyn and nedocromil are much less potent and have fewer side effects. Anti-inflammatory agents that are primarily used as immunosuppressive agents and anticancer agents (i.e., cytoxan, methotrexate and immuran) have also been used to treat inflammation. These agents, however, have serious side effect potential, including, but not limited to, increased susceptibility to infection, liver toxicity, drug-induced lung disease, and bone marrow suppression. Thus, such drugs have found limited clinical use for the treatment of most airway hyperresponsiveness lung diseases. Recently, a new approach to modulating or inhibiting the IgE response has been studied in humans. Anti-IgE monoclonal antibodies have been administered to asthmatic subjects in order to assess their efficacy in the early and late responses to allergen administration by inhalation in asthmatic subjects. The IV administration of such anti-IgE monoclonal antibodies significantly lowered serum IgE levels in 6 of 9 subjects and this resulted in attenuation of early-phase as well as the late-phase response. (The Effect of an Anti-IgE Monoclonal Antibody on the Early and Late Phase Response to Allergen Inhalation in Asthmatic Subjects. Fahy et al, Am J Respir Crit Care Med Vol. 155, pp 1828-1834, 1997. IgE inhibition as a Therapy for Allergic Disease, Jardieu, P and Fick, Robert, Int Arch Allergy Immunol 1999; 118: 112-115.) However, while this study showed that significant clinical response can be obtained using anti-IgE antibodies, the administration of this medication is by intravenous route that can be expensive and uncomfortable for the patients.